Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Intestinal anti-inflammatory agents; aminosalicylic acid and similar agents
ATC code: A07EC02

Mechanism of action
The mechanism of the anti-inflammatory action is unknown. The results of in vitro studies indicate that inhibition of lipoxygenase may play a role.

Effects on prostaglandin concentrations in the intestinal mucosa have also been demonstrated. Mesalazine (5-aminosalicylic acid / 5-ASA) may also function as a radical scavenger of reactive oxygen compounds.

Pharmacodynamic effects

Mesalazine, orally administered, acts predominantly locally at the gut mucosa and in the submucous tissue from the luminal side of the intestine. It is important, therefore, that mesalazine is available at the regions of inflammation. Systemic bioavailability/plasma concentrations of mesalazine therefore are of no relevance for therapeutic efficacy, but rather a factor for safety. In order to realise this, Rafassal Granules are gastric juice resistant and release mesalazine in a pH dependent manner, due to an Eudragit L coating, and prolonged manner, due to the matrix granule structure.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
General considerations of mesalazine:

Absorption:
Mesalazine absorption is highest in proximal gut regions and lowest in distal gut areas.
Biotransformation:
Mesalazine is metabolised both pre-systemically by the intestinal mucosa and the liver to the pharmacologically inactive N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA).
The acetylation seems to be independent of the acetylator phenotype of the patient. Some acetylation also occurs through the action of colonic bacteria.
Protein binding of mesalazine and N-Ac-5-ASA is 43 % and 78 %, respectively.

Elimination:
Mesalazine and its metabolite N-Ac-5-ASA are eliminated via the faeces (major part), renally (varies between 20% and 50 %, dependent on kind of application, pharmaceutical preparation and route of mesalazine release, respectively), and biliary (minor part). Renal excretion predominantly occurs as N-Ac-5-ASA. About 1 % of total orally administered mesalazine dose is excreted into the breast milk mainly as N-Ac-5-ASA.

Rafassal Granules specific:

Distribution:
Owing to the granule size of about 1 mm, transit from the stomach to the small intestine is fast.
A combined pharmacoscintigraphic/pharmacokinetic study showed that the compound reaches the ileocaecal region within approx. 3 hours and the ascending colon within approx. 4 hours. The total transit time in the colon amounts to about 20 hours.
Approximately 80 % of an administered oral dose is estimated to be available in the colon, sigmoid and rectum.

Absorption:
Mesalazine release from Rafassal Granules starts after a lag phase of about 2-3 hours, Peak plasma concentrations are reached at about 4-5 hours. The systemic bioavailability of mesalazine after oral administration is estimated to be approximately 15%-25%.
Food intake delays absorption for 1 to 2 hours but does not change the rate and extent of absorption.

Elimination:
From a 3 x 500 mg daily mesalazine dose, a total renal elimination of mesalazine and N-Ac-5-ASA under steady state condition was calculated to be about 25 %.
The un-metabolised excreted mesalazine part was less than 1 % of the oral dose.
The terminal elimination half-life observed after single dose adminstration of 3 * 500 mg or 3 * 1000 mg mesalazine was 4.4 10.5 hours.